5-hydroxy-dibenzocyclohepten-5-yl-carboxylates



United States Patent 3,527,763 S-HYDROXY-DIBENZOCYCLOI-IEPTEN- S-YL-CARBOXYLATES Cornelis van der Stelt, Haarlem, Netherlands, assignor to N.V. Koninklijke Pharmaceutische Fabrieken v/ h Brocades-Stheeman & Pharmacia, Amsterdam, Netherlands No Drawing. Original application Sept. 1, 1965, Ser. No. 484,420, now Patent No. 3,349,093. Divided and this application Apr. 26, 1967, Ser. No. 646,787

Int. Cl. C07d 39/06 US. Cl. 260294.3 3 Claims ABSTRACT OF THE DISCLOSURE This invention relates to new pharmaceutical compounds having the formula wherein X represents a --CH C-H or -CH=CH- group, R and R are the same or different and each represents a hydrogen or halogen atom or a lower alkyl group, and R represents a saturated polycyclic nitrogencontaining radical of up to twelve carbon atoms attached through carbon to the oxygen atom, and acid-addition salts thereof. These compounds possess anti-arythmetic and atropine-like activity.

This application is a divisional of application Ser. No. 484,420, filed Sept. 1, 1965, now U.S. Pat. 3,349,093.

This invention relates to new therapeutically useful esters of 5 hydroxydibenzocycloheptenyl carboxylic acids and their acid-addition salts, to processes for their preparation and to pharmaceutical preparations containing them.

According to the present invention, there are provided the new esters of 5 hydroxy 5H dibenzocyclohepten- 5-yl-carboxylic acids of the general formula:

OR: (I)

wherein X represents a -CH -CH or C-H=CH- group, R and R are the same or different and each represents a hydrogen or halogen atom or a lower alkyl group, and R represents a saturated polycyclic nitrogen-containing radical with from one to twelve carbon atoms attached through carbon to the oxygen atom, and acid-addition salts thereof. Examples of saturated polycyclic nitrogencontaining radicals which the symbol R may represent are S-tropanyl, N-lower alkyl-3 tropanyl, N-aryl(lower) alky1- 3 tropanyl, 3 granatyl, N-lower alkyl-3-granaty1, 6,7 epoxy 3 tropanyl, 6,7-epoxy-N-lower alkyl-3- tropanyl, 3 pseudotropanyl and 3 quinucl-idinyl. The term lower -alkyl group as employed in this specification means straight and branched chain alkyl groups of from one to six carbons.

The aforesaid esters of 5-hydroxydibenzocycloheptenylcarboxylic acids are therapeutically active compounds. They can be utilized as anti-arythmetic agents (i.e., compounds which influence the rhythm of the heart beat) and atropine-like agents. The compounds of the inven- 3,527,763 Patented Sept. 8., 1970 tion can be formulated for such administration, the concentration and/or dosage being based on the activity of the particular compound and the requirements of the patient. Generally, from about 50 mg. to mg. of compound per kg. of weight may be utilized the preferred dosage being from about 5 mg. to 10 mg. per kg. of weight. When used for therapeutic purposes they may be employed as such or in the form of non toxic acid-addition salts, i.e., salts which are not harmful to the animal organism when used in therapeutic doses. Such salts may be derived from inorganic acids, such as the hydrohalic acids (e.g., hydrochloric and hydrobromic acid), sulphuric acid, nitric acid and phosphoric acid, and organic acids such as oxalic, maleic, tartaric, citric, acetic, lactic, succinic, fumaric and pamoic acids. The preferred compounds of the invention are those wherein X represents a CH CH group, R is in the 3-position and represents a hydrogen or chlorine atom or a methyl group, R represents a hydrogen atom, and R represents a 3- tropanyl or 3-quinuclidinyl radical and their non-toxic acid-addition salts and, in particular, the quinuclidin-3-yl ester of 10,11 dihydro 5 hydroxy-5H-dibenzo[a,d] cyclohepten-S-carboxylic acid.

According to a feature of the invention, the compounds of Formula I are prepared by the esterification of an acid HO O O OH (II) wherein X, R, and R are as hereinbefore defined) or a reactive derivative thereof, such as an acid halide (preferably chloride), with an alcohol of the formula R OH, R being as hereinbefore defined. The reaction can be carried out by heating the reactants in the presence of an inert organic solvent, e.-g., dichloroethane, benzene, or purified light petroleum.

According to a modification of the aforesaid reaction, a halide R Y, wherein R is as hereinbefore defined and Y represents a halogen (preferably chlorine) atom, is reacted with an acid of Formula II. The reaction can be carried out by heating the reactants in an appropriate solvent such as a low boiling alcohol, e.-g., isopropanol.

According to a further modification of the reaction, an acid of Formula II is first converted into an ester, preferably an ester with a lower aliphatic alcohol such as the methyl ester, and the compounds of Formula I are then obtained by transesterification, i.e., by exchange of the ester group for the group R, by reaction with an alcohol R OH. The transesterification reaction is preferably carried out in the presence of sodium or sodium hydride. It is advantageous to effect the conversion in an inert organic solvent such as benzene, toluene or xylene.

The acids of Formula II can be obtained by reacting a ketone of the formula:

i (III) (wherein X, R, and R are as hereinbefore defined) with an alkali metal and then with carbon dioxide. The reaction is preferably conducted in a solvent such as dioxane. It is especially advantageous to use two molar equivalents of alkali metal (preferably sodium) per equivalent of ketone employed to increase the rate of reaction.

Examples of ketones of Formula III which may be used as starting materials are 10,1l-dihydro-5H-dibenzo [a,d]cyclohepten-5-one; 1,2,3 and 4-chloro-10,l1-dihydro- SH-dibenzo[a,d]cyclohepten--one; 1,2,3 and 4-bromo- 10,11-dihydro 5H dibenzo[a,d]cyclohepten-S-one; 1,2,3 and 4-methyl-10,1 l-dihydro-5H-dibenzo a,d] cyclohepten- 5-0ne; 1,2,3 and 4-ethyll0,ll-dihydro-SH-dibenzo[a,d] cyclohepten-S-one; 1,2,3 and 4-isopropyl-10,1l-dihydro- SH-dibenzo[a,d]cyclohepten-5-one; 1,2,3 and 4-t.butyl- 10,11 dihydro 5H-dibenzo[a,d]cyclohepten-S-one; 3,9-, 1,7- and 3,7-dimethyl 10,11 dihydro-5H-dibenzo[a,d] cyclohepten-S-one; 5H-dibenzo[a,d]cyclohepten 5 one; 1,2,3 and 4-chloro SH-dibenzo[a,d]cyclohepten-5-one; 1,2,3 and 4 bromo 5H-dibenzo[a,d] cyclohepten-S-one; 1,2,3 and 4 methyl SH-dibenzo [a,d] cyclohepten-S-one; 1,2,3 and 4-ethyl-5H-dibenzo [a,d]cyclohepten-5-one; 1,2,3 and 4-isopropyl-5H-dibenzo[a,d]cyclohepten-S-one; 1,2,3 and 4-t.butyl-5H-dibenzo[a,d]cyclohepten-S-one; 3,9-, 1,7- and 3,7-dimethyl-5H-dibenzo[a,d]cyclohepten-S-one. The above mentioned ketones insofar as they are presently unknown can be prepared according to the procedures described in British patent specification No. 943,604.

The acid halides and esters, e.g., lower alkyl esters, of the acids of Formula II can be prepared by methods known to the art.

The compounds of the invention when prepared by the aforementioned process or its modifications in the form of the free basic esters can be converted into corresponding acid-addition salts by a manner known to the art, e.g., by dissolving the ester in an inert anhydrous organic solvent and adding a solution of the desired acid preferably in the same or in a homogenously miscible solvent, and causing the salt to precipitate.

The following examples, in which the temperatures mentioned are in degrees centigrade, illustrate the preparation of esters of 5-hydroxy-5H-dibenzocycloheptenylcarboxylic acids of the present invention.

EXAMPLE 1 Quinuclidin-3-yl-5-hydroxy-10,1l-dihydro-SH-dibenzo [a,d] cyclohepten-S-carboxylate (a) To a solution of 15 g. of quinuclidin-3-ol in 60 ml. of anhydrous benzene, 13 g. of the methyl ester of 5-hydroxy-10,1l-dihydro-SH dibenzo[a,d]cyclohepten-5- carboxylic acid and 0.4 g. of a 50% sodium hydride suspension in a mineral oil are added carefully. Transesterification of the acid is carried out azeotropically. Water with benzene is distilled off and replaced with anhydrous benzene at the same rate for about four hours. After cooling the remaining sodium hydride is decomposed by the addition of 20 ml. of water. The aqueous layer is separated and the benzene layer is washed with water.

The quinuclidin-3-yl ester of 5-hydroxy-10,11-dihydro- SH-dibenzo[a,d]cyclohepten-S-carboxylic acid is precipitated by the addition of diethyl ether and petroleum ether (boiling range 28-40). The ester is filtered off and washed with water and diethyl ether. The combined organic layers are treated with a dilute hydrochloric acid solution. The acidic aqueous solution is made alkaline and the precipitated solid yields a second crop of ester. Total yield is 16 g. (89%) of ester product, melting at 190. The melting point can be raised to 204-206 by crystallization of the ester from dioxane.

Analysis.Calcd for C H NO C, 76.02%; H, 6.93%; N, 3.88%. Found: C, 75.90%, H, 7.28%; N, 3.75%.

(b) The methyl-5-hydroxy-10,11 dihydro-SH-dibenzo [a,d] cyclohepten-S-carboxylate employed as starting material is prepared as follows:

A mixture of 500 ml. of anhydrous dioxane and 47 g. of sodium is heated until the dioxane boils under reflux and the sodium melts. The mixture is stirred vigorously and 250 ml. of anhydrous dioxane is added. The temperature drops to about 90 and the sodium, divided into small particles, becomes solid again. The mixture is cooled to room temperature and 200 g. of 10,11-dihydro-5H- dibenzo[a,d]cyclohepten-S-one are added. The temperature is kept below 20 during the addition. Carbon dioxide is introduced together with 500 ml. of tetrahydrofuran until the blue color disappears. Small lumps of solid carbon dioxide and water are added until all solid material is dissolved. The clear solution is concentrated under reduced pressure to about half its original volume and extracted with ether. The aqueous layer is acidified with a 2 N hydrochloric acid solution. 5-Hydroxy-10,11-dihydro 5H dibenzo[a,d]cyclohepten-S-carboxylic acid precipitates and is filtered off. Yield: 230 g. of product, melting at l90.

The methyl ester is prepared from the acid in the following way:

An ethereal solution of diazomethane is added to a solution of S-hydroxy 10,11 dihydro-5H-dibenzo[a,d] cyclohepten-S-carboxylic acid in the same solvent until a yellow color persists. Excess of diazomethane is destroyed by the addition of a solution of acetic acid in ether. The solution is washed with a dilute sodium bicarbonate solution, thereafter with water and dried with sodium sulphate. After filtration the solvent is distilled off and the residue is crystallized from carbon tetrachloride. Yield of methyl ester: g. (90%); melting point 138-140.

EXAMPLE 2 3-tropanyl-5hydroxy- 10, 1 l-dihydroxy-SH-dibenzo [a,d] cyclohepten-S-carboxylate Following the procedure described in step (a) of Example 1 but substituting an equivalent amount of tropine for the quinuclidin-3-ol, the 3-tropanyl ester of S-dihydroxy-10,l1-dihydro 5H-dibenzo[a,d]cyclohepten-S-carboxylic acid is obtained in 30% yield. Melting point of the ester is 200202.

Analysis.-Calcd for C H NO C, 76.30%; H, 7.21%; N, 3.71%. Found: C, 76.42%; H, 7.08%; N, 3.97%.

EXAMPLE 3 Quinuclidin-3-yl-S-hydroxy-SH-dibenzo [a,d] cyclohepten- S-carboxylate (a) Following the procedure described in step (a) of Example 1 but substituting an equivalent amount of the methyl ester of S-hydroxy-SH-dibenzo[a,d]cyclohepten- S-carboxylic acid for the methyl ester of 5-hydroxy-10,1ldihydro-SH-dibenzo[a,d]cyclohepten-5 carboxylic acid, the quinuclidin-3-yl ester of 5-hydroxy-5H-dibenzo[a,d] cyclohepten-S-carboxylic acid is obtained in 66% yield. Its melting point is 257259, and its maleate melts at 182- 184 C.

Analysis.Calcd for C27H27O7N (percent): C, 67.91; H, 5.70; N, 2.94. Found (percent): C, 67.9; H, 5.8; N, 3.1.

65% yield following the procedure described in step (b) of Example 1 but substituting an equivalent amount of SH-dibenzo[a,d]cyclophepten-5-one for the 10,11-dihydro-SH-dibenzo[a,d]cyclohepten-5-one.

EXAMPLE 4 3-Tropanyl-5-hydroxy-5H-dibenzo [a,d] cyclohepten-S- carboxylate Following the procedure described in step (a) of Example 1 "but substituting an equivalent amount of tropine for the quinuclidin-3-ol and the methyl ester of S-hydroxy-SH- dibenzo[a,d]cyclohepten-S-carboxylic acid for the methyl ester of 10,1l-dihydro-S-hydroxy-SH dibenzo[a,d]cyclohepten-S-carboxylic acid, the 3-tropanyl ester of 5-hydroxy-SH-dibenzo [a,d]cyclohepten-S-carboxylic acid is obtained in 30% yield. Melting point 248250.

Analysis.Calcd for C H NO (percent): C, 76.76; H, 6.71; N, 3.74. Found (percent): C, 76.40; H, 6.59; N, 4.00.

Similarly, if an R and/ or R -substituted 10,11-dihydro- 5 hydroxy-SH-dibenzo [a,d]cyclohepten-S-carboxylic acid alkyl ester is substituted for the 10,11-dihydro-5-hydroxy- The methyl ester starting material is obtained in v SH-dibenzo[a,d]cycloheptencarboxylic acid methyl ester in Example 1, the corresponding quinuclidin-3 yl ester of the R and/or R substituted-10,1I-dihydro-S-hydroxy-SH-dibenzo[a,d]cyclohepten-5 carboxylic acid is obtained. Moreover, if an R and/or R substituted 5- hydroxy-SH-dibenzo[a,d]cyclohepten-5 carboxylic acid alkyl ester is substituted for the S-hydroxy-SH-dibenzo [a,d]cyclohepten-S-carboxylic acid methyl ester in Example 1, the corresponding quinuclidin-3-y1 ester of the R and/or R substituted-S-hydroxy-SH dibenzo[a,d1 cyclohepten-S-carboxylic acid is obtained.

The invention includes Within its scope pharmaceutical preparations containing, as the active ingredient, at least one of the therapeutically active compounds of general Formula I, or non-toxic acid-addition salt thereof, in association with a pharmaceutically-acceptable carrier. The preparations may take any of the forms customarily employed for administration of therapeutically active substances, but the preferred types are those suitable for oral administration and especially tablets, including sustained release tablets, pills and capsules including the substance. The tablets and pills may be formulated in the usual manner with one or more pharmaceutically-acceptable diluents or excipients, for example, lactose or starch, and include materials of a lubricating nature, for example, calcium or magnesium stearate. Capsules made of absorbable material, such as gelatin, may contain the active substance alone or in admixture with a solid or liquid diluent. Liquid preparations may be in the form of suspensions, emulsions, syrups or elixirs of the active substance in water or other liquid medium commonly used for making orally acceptable pharmaceutical formulations, such as liquid parafiin, or a syrup or elixir base. The active substance may also be made up in a form for parenteral administration, i.e., as a suspension or emulsion in sterile water or an organic liquid usually employed for injectable preparations, for example, a vegetable oil such as olive oil, or a sterile solution in an organic solvent.

While there have been described various embodiments of the invention, the compositions and methods described are not intended to be understood as limiting the scope of the invention, as it is realized that changes therein are possible and it is further intended that each element recited in any of the following claims is to be understood as referring to all equivalent elements for accomplishing substantially the same results in substantially the same or equivalent manner, it covering the invention broadly in whatever form its principle may be utilized.

What is claimed is:

1. A compound having the formula wherein X is CH CH or CH=CH, R and R are hydrogen, halogen or lower alkyl, and R is 3- granatyl, N-lower alkyl 3-granatyl or 3-quinuclidinyl, and non-toxic acid-addition salts thereof.

2. Quinuclidin-3-yl-5-hydroxy-10,1l-dihydro 5H dibenzo [a,d] cyclohepten-S-carboxylate.

3. Quinuclidin-3-yl-5-hydroxy-5H dibenzo[a,d]cyclohepten-S-carboxylate.

References Cited UNITED STATES PATENTS 8/1966 Van der Stelt 260-292 OTHER REFERENCES Davis et al., J. Med. Chem. 6, 513-16 (1963).

HENRY R. J ILES, Primary Examiner G. THOMAS TODD, Assistant Examiner 

